Synthesis and in vivo antitumor activity of 2-amino-9H-purine-6-sulfenamide, -sulfinamide, and -sulfonamide and related purine ribonucleosides.
A number of 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide derivatives of 2-aminopurine and certain related purine ribonucleosides have been synthesized and evaluated for antileukemic activity in mice. Amination of 6-mercaptopurine ribonucleoside (7a) and 6-thioguanosine (7b) with chloramine solution gave 9-beta-D-ribofuranosylpurine-6-sulfenamide (8a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide (sulfenosine, 8b), respectively. Selective oxidation of 8a and 8b with 3-chloroperoxybenzoic acid (MCPBA) gave (R,S)-9-beta-D-ribofuranosylpurine-6-sulfinamide (9a) and (R,S)-2-amino-9-beta-D-ribofuranosylpurine-6-sulfinamide (sulfinosine, 9b), respectively. However, oxidation of 8a and 8b with excess of MCPBA gave 9-beta-D-ribofuranosylpurine-6-sulfonamide (10a) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfonamide (sulfonosine, 10b), respectively. Similarly, amination of 5'-deoxy-6-thioguanosine (7c) afforded the 6-sulfenamide derivative (8c), which on controlled oxidation gave (R,S)-2-amino-9-(5-deoxy-beta-D-ribofuranosyl)purine-6-sulfinamide (9c) and the corresponding 6-sulfonamide derivative (10c). Treatment of 6-thioguanine (12) with aqueous chloramine solution gave 2-amino-9H-purine-6-sulfenamide (13). Oxidation of 13 with 1 molar equiv of MCPBA afforded (R,S)-2-amino-9H-purine-6-sulfinamide (14), whereas the use of 4 molar equiv of MCPBA furnished 2-amino-9H-purine-6-sulfonamide (15). The resolution of R and S diastereomers of sulfinosine (9b) was accomplished by HPLC techniques. The structures of (R)-9b and 10b were assigned by single-crystal X-ray diffraction studies. (R)-9b exists in the crystal structure in four crystallographically independent conformations. Of the 18 compounds evaluated, 13 exhibited very significant anti-L1210 activity in mice. Sulfenosine (8b) at 22 mg/kg per day X 1 showed a T/C of 170, whereas sulfinosine (9b) at 173 mg/kg per day X 1 showed a T/C of 167 against L1210 leukemia. The 5'-deoxy analogue of sulfinosine (9c) at 104 mg/kg per day also showed a T/C of 172. A single treatment with 8b, 9b, and 9c reduced body burdens of viable L1210 cells by more than 99.8%.
Revankar
G R
GR
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Hanna
N B
NB
Imamura
N
N
Lewis
A F
AF
Larson
S B
SB
Finch
R A
RA
Avery
T L
TL
Robins
R K
RK
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D000225:Adenine / Q000031:analogs & derivatives*; D000818:Animals; D000970:Antineoplastic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000627:therapeutic use*; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000627:therapeutic use*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000627:therapeutic use*; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D012263:Ribonucleosides; D013449:Sulfonamides; D015075:2-Aminopurine; D000225:Adenine